Hairy leukoplakia (HLP) is a common opportunistic infection in human immunodeficiency virus (HIV)-infected individuals. HLP occurs on the lateral tongue and is caused by the Epstein-Barr virus (EBV). HLP is remarkable as the only pathologic manifestation of productive EBV infection and as the only non-malignant lesion of epithelial cell EBV infection. HLP offers insight into the mechanisms of EBV persistence and the role of specific EBV gene products in HIV-associated EBV pathogenesis. Three hypotheses will be tested: 1) That tongue epithelial cells are a second reservoir of persistent EBV infection in HIV-infected individuals. 2) That HLP results from a unique co-expression of both latent and productive EBV genes. 3) That novel molecular mechanisms regulate the unique pattern of EBV gene expression seen in HLP. In a clinical study protocol, HIV-infected volunteers with HLP will be treated with antiviral therapy to inhibit EBV replication and induce BV latency. Subsequent withdrawal of antiviral therapy will permit EBV reactivation. Tongue and blood lymphocyte tissues will be collected before, during, and after antiviral therapy. Molecular studies will investigate the molecular biology and epidemiology of EBV latency and reactivation. The role of gene expression in EBV pathogenesis will be investigated, including the functional consequences of EBV gene sequence variation and genetic recombination in HLP. Finally, the role of HIV-EBV interaction in HLP pathogenesis will be investigated. The results of this study will elucidate molecular mechanisms of EBV pathogenesis in HLP applicable to other EBV-associated diseases, including nasopharyngeal carcinoma and HIV-associated lymphomas.